Synthesis and pharmacological investigation of novel 1-substituted-4-(4- substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents

Article abstract of DOI:10.1211/jpp.58.9.0012

A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4] triazolo[4,3-a]quinazolin-5-ones was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with various one-carbon donors. The starting material, 2-hy

Full text of DOI:10.1211/jpp.58.9.0012

JPP 2006, 58: 1249–1255
© 2006 The Authors
Received February 17, 2006
Accepted May 26, 2006
DOI 10.1211/jpp.58.9.0012
ISSN 0022-3573
Synthesis and pharmacological investigation
of novel 1-substituted-4-(4-substituted phenyl)-4H-
[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new
class of H1-antihistamine agents
V. Alagarsamy, Rajani Giridhar and M. R. Yadav
Abstract
A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones
was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with
various one-carbon donors. The starting material, 2-hydrazino-3-(4-substituted phenyl)-3H-quinazo-
lin-4-one, was synthesized from 4-substituted aniline by a novel innovative route. When tested for
in-vivo H1-antihistamine activity on conscious guinea-pigs, all the test compounds significantly pro-
tected the animals against histamine-induced bronchospasm. The compound 1-methyl-4-(4-chloro
phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (VII) was more potent (72.71% protection), and
1-methyl-4-(4-methoxy phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was equipotent (71%
protection), when compared with the reference standard, chlorpheniramine maleate (71% protec-
tion). Compounds II and VII showed negligible sedation (5% and 8% respectively) when compared
with chlorpheniramine maleate (25%). Compounds II and VII could serve as prototype molecules for
further development as a new class of H1-antihistamines.
Introduction
First generation antihistamines penetrate the blood–brain barrier and also possess anti-
cholinergic properties; this has led to the development of a second generation of H1-antago-
nists (Simons & Simons 1994) such as terfenadine, cetirizine and astemizole. A common
feature of first generation compounds is two aryl or heteroaryl rings linked to an aliphatic
tertiary amine via the side chain (Ellis et al 1985) (e.g. diphenhydramine and pheniramine).
The second generation compounds (terfenadine and cetirizine) also contain many of the
structural features of first generation compounds. The real breakthrough of non-sedative
antihistamines came in the early 1980s with the discovery of modern antihistamines that
exhibit potent antihistamine activity without sedative effects (Carr & Meyer 1982). Con-
densed heterocycles containing a new generation of H1-antihistamines (e.g. loratadine,
azelastine and flazelastine) that do not possess the above-mentioned pharmacophore for
H1-antihistamines gave way to the discovery of many novel antihistamines such as temelas-
tine (Mc Call et al 1985) and mangostin (Chirungsrilerd et al 1987). Quinazolines and con-
densed quinazolines show excellent antihistamine activity (Wade 1984; West & July 1981).
Continuing our search for quinazoline derivatives with potent antihistamine activity and
reduced sedative effects (Alagarsamy et al 2002; Alagarsamy 2004), we aimed to prepare a
series of 1,2,4-triazolo-4H-[4,3-a]quinazolin-5-ones containing 4-substituted phenyl substi-
tution at position 4 and alkyl substitution at position 1. The title compounds were synthe-
sized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one (6)
with various one-carbon donors. The 2-hydrazino-3-(4-substituted phenyl)-3H-quinazo-
lin-4-one (6) was synthesized from 4-substituted aniline (1) by a novel innovative route.
Spectral data (IR, NMR and mass spectra) confirmed the structures of the synthesized com-
pounds; the purity of the compounds was determined by microanalysis. The synthesized
compounds were tested for their in-vivo H1-antihistamine activity in conscious guinea-pigs.
As sedation is one of the major side-effects associated with antihistamines, the test
Medicinal Chemistry Research
Laboratory, Arulmigu
Kalasalingam College of
Pharmacy, Anand Nagar,
Krishnan koil-626 190, India
V. Alagarsamy
Department of Pharmacy,
Faculty of Technology and
Engineering, The MS University
of Baroda, Baroda-390 001, India
R. Giridhar, M. R. Yadav
Correspondence: V. Alagarsamy,
Medicinal Chemistry Research
Laboratory, Arulmigu
Kalasalingam College of
Pharmacy, Anand Nagar,
Krishnan koil-626 190,
Tamilnadu State, India.
E-mail: samy_veera@yahoo.com
1249

1250
V. Alagarsamy et al
compounds were also evaluated for their sedative potential by into ice water. The solid obtained was filtered, washed with
measuring the reduction in locomotor activity using an acto- water, dried and recrystallized from an ethanol/chloroform
photometer.
(75:25) mixture. Yield 78%, mp 142–145°C; IR (KBr) cm−1:
1
1683 (C=O), 1610 (C=C); H NMR (CDCl3) d (ppm): 2.5
(s, 3H, SCH3), 3.87 (s, 3H, OCH3), 7.0–8.26 (m, 8H ArH);
MS (m/z): 298 [M+]; Anal. calcd for C16H14N2O2S: C, 64.41;
H, 4.72; N, 9.38. Found: C, 64.53; H, 4.67; N, 9.45.
Materials and Methods
Chemistry
2-Methylsulfanyl-3-(4-chlorophenyl)-3H-
quinazolin-4-one (5b)
Melting points were determined in open capillary tubes on a
Thomas Hoover apparatus and are uncorrected. IR spectra
were recorded in KBr on a Shimadzu FT-IR, 8300 spectrome-
ter (cm−1), mass spectra were recorded on a MASPEC msw
9629 mass spectrometer at 70 eV, and 1HNMR spectra were
recorded on a Varian 300 MHz spectrometer, using tetrameth-
ylsilane as internal standard. Elemental analyses were performed
on a Carlo erba 1108 instrument.
This was prepared using the method described above. Yield
80%, mp 136–139°C; IR (KBr) cm−1: 1680 (C=O); 1H NMR
(CDCl3) d (ppm): 2.7 (s, 3H, SCH3), 7.3–8.4 (m, 8H ArH);
MS (m/z): 302 [M+], 304 [M++2]; Anal. calcd for
C15H11N2OSCl: C, 59.50; H, 03.66; N, 9.25. Found: C,
59.53; H, 03.61; N, 9.31.
2-Hydrazino-3-(4-methoxyphenyl)-3H-quinazolin-
4-one (6a)
3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydro-1H-
quinazolin-4-one (4a)
2-Methylsulfanyl-3-(4-methoxyphenyl)-3H-quinazolin-4-one
(5a) (0.01 mol) was dissolved in ethanol (25 mL). To this,
hydrazine hydrate (99%) (0.1 mol) and anhydrous potassium
carbonate (100 mg) was added and refluxed for 30 h. The
reaction mixture was cooled and poured into ice water. The
solid obtained was filtered, washed with water, dried and
recrystallized from a chloroform/benzene (25:75) mixture.
Yield 74%, mp 196–200°C; IR (KBr) cm−1: 3350, 3320
A solution of 4-methoxy aniline (1) (0.02 mol) in dimethyl-
sulfoxide (DMSO) (10 mL) was stirred vigorously. To this
was added carbon disulfide (1.6 mL) and aqueous sodium
hydroxide (1.2 mL; 20 mol) dropwise during 30 min with stir-
ring. Dimethylsulfate (0.02 mol) was added gradually, keep-
ing the reaction mixture stirred in freezing mixture for 2 h.
The reaction mixture was then poured into ice water. The
solid obtained was filtered, washed with water, dried and
recrystallized from ethanol. Methyl anthranilate (0.01 mol)
and the above-prepared N-(4-methoxyphenyl)-methyl dithio-
carbamic acid (0.01 mol) were dissolved in ethanol (20 mL).
Anhydrous potassium carbonate (100 mg) was then added
and refluxed for 21 h. The reaction mixture was cooled in ice.
The solid separated was filtered and purified by dissolving in
10% alcoholic sodium hydroxide solution and reprecipitated
by treating with dilute hydrochloric acid. The solid obtained
was filtered, washed with water, dried and recrystallized from
ethanol. Yield 80%, mp 296–300°C; IR (KBr) cm−1: 3218
(NH), 1680 (C=O), 1593 (C=C), 1200 (C=S); 1H NMR
(CDCl3) d (ppm): 3.88 (s, 3H, OCH3), 7.0–8.1 (m, 8H, ArH),
10.36 (s, 1H, NH); MS (m/z): 284 [M+]. Anal. calcd for
C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.29;
H, 4.21; N, 9.91.
1
(NHNH2), 1674 (C = O); H NMR (CDCl3) d (ppm): 3.79
(s, 3H, OCH3), 4.95 (s, 2H, NH2), 6.82–8.06 (m, 8H, ArH),
8.56 (s, 1H, NH); MS (m/z): 282 [M+]; Anal. calcd for
C15H14N4O2: C, 63.82; H, 4.99; N, 19.84. Found: C, 63.71;
H, 4.95; N, 19.93.
2-Hydrazino-3-(4-chlorophenyl)-3H-quinazolin-4-
one (6b)
This was prepared using the method described above. Yield
83%, mp 162–165°C; IR (KBr) cm−1: 3360, 3300 (NHNH2),
1
1680 (C= O); H NMR (CDCl3) d (ppm): 4.98 (s, 2H, NH2),
6.93–8.12 (m, 8H, ArH), 8.73 (s, 1H, NH); MS (m/z): 286
[M+], 320 [M++2]; Anal. calcd for C14H11N4OCl: C, 58.64;
H, 03.86; N, 19.54. Found: C, 58.60; H, 03.82; N, 19.59.
4-(4-Methoxyphenyl)-4H-[1,2,4] triazolo [4,3-a]
quinazolin-5-one (I)
3-(4-Chlorophenyl)-2-thioxo-2,3-dihydro-1H-
quinazolin-4-one (4b)
The 2-hydrazino-3-(4-methoxyphenyl)-3H-quinazolin-4-one
(6a) (0.01 mol) and formic acid (25 mL) were mixed in a
round-bottomed flask and refluxed for 34 h, cooled and
poured into ice water. The solid obtained was filtered, washed
with water, dried and recrystallized from ethanol. IR (KBr)
This was prepared using the method described above. Yield
74%, mp 319–321°C. IR (KBr) cm−1: 3210 (NH), 1690
(C=O), 1210 (C=S); 1H NMR (CDCl3) d (ppm): 7.5–8.2
(m, 8H, ArH), 10.36 (s, 1H, NH); MS (m/z): 288 [M+], 290
[M++2]. Anal. calcd for C14H9N2OSCl: C, 58.23; H, 03.14;
N, 9.70. Found: C, 58.32; H, 03.11; N, 09.74.
1
cm−1: 1684 (C=O), 1607 (C=N); H NMR (CDCl3) d (ppm):
3.9 (s, 3H, OCH3), 7.1–8.4 (m, 8H, ArH), 8.6–8.7 (s, 1H,
ArH); MS (m/z): 292 [M+]. Using this procedure, compounds
II–X were prepared.
2-Methylsulfanyl-3-(4-methoxyphenyl)-3H-
quinazolin-4-one (5a)
The 3-(4-methoxyphenyl)-2-thioxo-2,3-dihydro-1H-quinazo-
lin-4-one (4a) (0.01 mol) was dissolved in 40 mL of 2% alco-
1-Methyl-4-(4-methoxyphenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (II)
holic sodium hydroxide solution. To this, dimethylsulfate IR (KBr) cm−1: 1707 (C=O), 1605 (C=N); 1H NMR (CDCl3)
(0.01 mol) was added dropwise with stirring. Stirring was d (ppm): 2.5–2.6 (s, 3H, CH3), 3.6–3.7 (s, 3H, OCH3), 7.0–8.1
continued for 1 h and the reaction mixture was then poured (m, 8H, ArH); MS (m/z): 306 [M+].

Novel H1-antihistamine agents
1251
synthesized compounds. Male Dunkin Hartley guinea-pigs
(250–300g) were fasted for 12 h. There were six animals in
each group. The test compounds was administered orally at a
dose of 10mg kg−1 in 1% CMC and challenged with histamine
aerosol (3mL of a 0.2% aqueous solution of histamine acid
chloride) in a vaponephrin pocket nebulizer sprayed into a
closed transparent cage. The respiratory status, reflecting the
increasing degree of bronchoconstriction, was recorded. The
time of onset of convulsions (pre-convulsion) was recorded.
Animals remaining stable for more than 6 min were consid-
ered protected against histamine-induced bronchospasm. The
test animals were given an intraperitoneal injection of chlor-
pheniramine maleate (Avil; Hoechst, Mumbai, India) at a dose
of 25mg kg−1 for their recovery. The mean pre-convulsion time
of animals treated with the test compounds was compared with
the control and expressed in terms of percentage protection:
1-Ethyl-4-(4-methoxyphenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (III)
IR (KBr) cm−1: 1684 (C=O), 1601 (C=N); 1HNMR (CDCl3) d
(ppm): 1.3–1.35 (t, 3H, CH2CH3), 2.69–2.76 (q, 2H, CH2CH3),
3.9 (s, 3H, OCH3), 7.1–8.4 (m, 8H, ArH); MS (m/z): 320 [M+].
1-Propyl-4-(4-methoxyphenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (IV)
IR (KBr) cm−1: 1683 (C=O), 1602 (C=N); 1H NMR (CDCl3)
d (ppm): 0.6–0.7 (t, 2H, CH2CH2CH3), 1.2–1.3 (sext, 2H,
CH2CH2CH3), 2.0–2.1 (t, 3H, CH2CH2CH3), 3.2–3.3 (s, 3H,
OCH3), 7.1–8.0 (m, 8H, ArH); MS (m/z): 334 [M+].
1-Chloromethyl-4-(4-methoxyphenyl)-4H-[1,2,4]
triazolo [4,3-a] quinazolin-5-one (V)
IR (KBr) cm−1: 1709 (C=O), 1605 (C=N); 1H NMR (CDCl3)
d (ppm): 3.9 (s, 3H, OCH3), 4.2–4.3 (s, 2H, CH2), 7.3–8.2 (m,
8H, ArH); MS (m/z): 340 [M+], 342 [M++2].
% protection = [1 – (T1 / T2)] × 100
where T2 is the pre-convulsive time of the test compound, and
T1 is the pre-convulsive time of the control. The activity of
the test compounds was compared with the standard
antihistamine chlorpheniramine maleate.
4-(4-Chlorophenyl)-4H-[1,2,4] triazolo [4,3-a]
quinazolin-5-one (VI)
IR (KBr) cm−1: 1682 (C=O); 1H NMR (CDCl3) d (ppm): 7.2–
8.0 (m, 8H, ArH), 8.8–8.9 (s, 1H, ArH); MS (m/z): 296 [M+],
298 [M++2].
Sedative/hypnotic activity
Sedative/hypnotic activity was determined by measuring the
reduction in locomotor activity using an actophotometer (Dews
1953; Khun & Van Mannen 1961). Swiss albino mice were used
in groups of six animals. The basal activity score was taken and
then compounds I–X and the standard chlorpheniramine maleate
were administered orally at a dose of 5 mg kg−1 in 1% CMC.
Scores were recorded at 0.5, 1, 2 and 3 h after the drug admin-
istration. The Student’s t-test was performed to determine the
significance of the exhibited activity. The percentage reduction
in locomotor activity was calculated by the following formula:
1-Methyl-4-(4-chlorophenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (VII)
IR (KBr) cm−1: 1688 (C=O), 1609 (C=N); 1H NMR (CDCl3)
d (ppm): 3.0–3.1 (s, 3H, CH3), 7.3–7.4 (m, 4H, ArH), 7.5–7.8
(m, 4H, ArH); MS (m/z): 310 [M+], 312 [M++2].
1-Ethyl-4-(4-chlorophenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (VIII)
IR (KBr) cm−1: 1688 (C=O), 1631 (C=N); 1HNMR (CDCl3) d
(ppm): 1.34–1.38 (t, 3H, CH2CH3), 2.72–2.79 (q, 2H, CH2CH3),
7.27–8.45 (m, 8H, ArH); MS (m/z): 324 [M+], 326 [M++2].
% reduction in motor activity = [(A – B)/A] × 100,
1-Propyl-4-(4-chlorophenyl)-4H-[1,2,4] triazolo
[4,3-a] quinazolin-5-one (IX)
where A is the basal score, and B is the score after drug treat-
ment.
IR (KBr) cm−1: 1689 (C=O), 1606 (C=N); 1HNMR (CDCl3) d
(ppm): 0.8–1.0 (t, 2H, CH2CH2CH3), 1.6–1.8 (sext, 2H,
CH2CH2CH3) 2.6–2.8 (t, 3H, CH2CH2CH3.), 7.2–8.5 (m, 8H,
ArH); MS (m/z): 338 [M+], 340 [M++2].
Statistical analysis
Statistical analysis of the biological activity of the synthe-
sized compounds was evaluated using a one-way analysis of
variance. In all cases, post-hoc comparisons of the means of
individual groups were performed using Tukey’s test. A level
of P < 0.05 denoted significance in all cases. All values are
expressed as mean s.d. GraphPad Prism version 3.0 was
used for statistical analysis (GraphPad Software, San Diego,
CA, USA).
1-Chloromethyl-4-(4-chloro phenyl)-4H-[1,2,4]
triazolo [4,3-a] quinazolin-5-one (X)
IR (KBr) cm−1: 1690 (C=O), 1609 (C=N); 1HNMR (CDCl3) d
(ppm): 4.6–4.7 (s, 2H, CH2), 7.3–8.5 (m, 4H, ArH), 7.6–7.7
(m, 4H, ArH); MS (m/z): 345 [M+], 347 [M++2].
Pharmacology
The antihistamine and sedative/hypnotic activity protocols
were approved by the institutional animal ethics committee
(approval no. SBCP/56/15/2002-2003).
Results and Discussion
The key intermediate 3-(4-substituted phenyl)-2-thioxo-2,3-
dihydro-1H-quinazolin-4-one (4) was prepared by refluxing
methyl anthranilate with 4-substituted phenyl isothiocyanate in
ethanol (Figure 1). However, the preparation of 4-substituted
Antihistamine activity
A modification of the technique of Van Arman et al (1960)
was adopted to determine the antihistamine potential of the

1252
V. Alagarsamy et al
O
O
OCH3
OCH3
EtOH
+
N=C=S
R
N
H
C
S
N
H
NH2
R
O
N
R
N
S
H
4
Figure 1 Synthesis of 3-(4-substituted phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one from 4-(substituted phenyl) isothiocyanate.
Acetone
S
S
NH2
+
+
R
CS2
K2CO3
C
NH
R
-
K +
1
(CH3)2SO4
O
O
OCH3
EtOH
OCH3
S
S
C
+
NH
R
CH3
N
H
C
S
N
H
R
NH2
2
3
3a
O
R
N
N
S
H
4
Figure 2 Synthesis of 3-(4-substituted phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one from 4-substituted aniline.
phenyl isothiocyanate required for the reaction was a tedious (2). Compound 2 on reflux with methyl anthranilate (3)
and time-consuming process and the yield was also low (60%). yielded 4. This process of synthesizing 4 suffers from the
An alternate route to synthesize 4 was attempted (Figure 2). following drawbacks: it is a multistep process, it requires pro-
In this route, 4-substituted aniline (1) was reacted with carbon longed reaction time (37 h) and the yield is also very low
disulfide and anhydrous potassium carbonate in acetone to (30%). The method was therefore modified. Aqueous sodium
give potassium dithiocarbamate, which was methylated with hydroxide (20 mol solution) was used as a base instead of
dimethylsulfate to afford dithiocarbamic acid methyl ester anhydrous K2CO3, and DMSO was substituted for acetone as

Novel H1-antihistamine agents
1253
the reaction solvent (Figure 3). The use of DMSO as the reac- 3218 cm−1 for cyclic thio urea (NH), 1680 cm−1 for carbonyl
tion solvent enhanced the rate of reaction and the use of the (C=O), and 1200 cm−1 for thioxo (C=S) stretching. The
alkali in a higher concentration helped to prevent hydrolysis 1H NMR spectrum of 4 showed a singlet at d 3.88 ppm due to
of the intermediate, probably owing to less solvation. These the OCH3 group, a multiplet at d 7–8.1 ppm for aromatic (8H)
modifications reduced the reaction time from 37 h to 23 h, and protons, and a singlet at d 10.36 ppm, indicating the presence
also increased the yield from 30% to 80%.
of NH. Data from the elemental analyses were found to be in
Thus, 4-substituted aniline (1) was treated with carbon accord with the assigned structure. Further, the molecular ion
disulfide and sodium hydroxide in DMSO to give sodium recorded in the mass spectrum was also in agreement with the
dithiocarbamate, which was methylated with dimethyl sulfate molecular weight of the compound.
to afford the dithiocarbamic acid methyl ester (2). Compound
The 2-methylsulfanyl-3-(4-substituted phenyl)-3H-quina-
2, on reflux with methyl anthranilate (3) in ethanol, yielded zolin-4-one 5 was obtained by dissolving 4 in 2% alcoholic
the desired 3-(4-substituted phenyl)-2-thioxo-2,3-dihydro- sodium hydroxide solution and methylating with dimethyl
1H-quinazolin-4-one (4) via the thiourea intermediate in a sulfate with stirring at room temperature. The IR spectrum of
good yield (80%). The product obtained was cyclic and not 5 showed disappearance of NH and C=S stretching signals of
an open chain thiourea 3a. It was confirmed by its low Rf cyclic thiourea. It showed a peak for carbonyl (C=O) stretch-
1
value, high melting point and its solubility in sodium hydrox- ing at 1683 cm−1. The H NMR spectrum of compound 5
ide solution. The IR spectrum of 4 showed intense peaks at showed singlets at d 2.5 ppm and 3.87 ppm due to SCH3 and
S
S
DMSO
NH2
+
+
R
CS2
NaOH
C
NH
R
-
+
Na
1
(CH3)2SO4
O
O
OCH3
EtOH
OCH3
S
S
C
+
NH
R
CH3
N
H
C
S
N
R
NH2
2
H
3
3a
O
N
O
R
R
N
N
NaOH / EtOH
(CH3)2SO4
SCH3
N
S
H
5
4
EtOH
.
NH2NH2 H2O
O
N
O
R
N
R
N
One carbon donors
N
N
N
NH
NH2
R
I X
6
Figure 3 Synthesis of 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-ones.

1254
V. Alagarsamy et al
OCH3, respectively, and a multiplet at d 7.0–8.26 ppm was IR spectra of all the compounds I–X. The 1H NMR spectra of
observed for aromatic (8H) protons. Data from the elemental I–X showed the absence of NH and NH2 signals. In the IR
analyses and molecular ion recorded in the mass spectrum spectra, these compounds showed a peak for carbonyl (C=O)
1
further confirmed the assigned structure.
around 1680 cm−1. The H NMR spectra of compounds I–X
Nucleophilic displacement of the methylthio group of 5 with showed a multiplet around d 7.0–8.5 ppm integrating for
hydrazine hydrate was carried out using ethanol as solvent to aromatic protons. The mass spectra of the title compounds
afford 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4- were in accord with the assigned structure. The mass spectra
one 6. The long time required for the reaction (30h) might be of these compounds showed molecular ion peaks correspond-
due to the presence of a bulky aromatic ring at position 3, which ing to their molecular formulae. The M++2 peaks were
might have reduced the reactivity of the quinazoline ring system observed in the spectra of compounds 4b, 5b, 6b and V–X,
at the C-2 position. The formation of 6 was confirmed by the confirming the presence of a chlorine atom in the compounds.
presence of NH and NH2 signals at 3350–3320cm−1 in the IR The relative intensities of these M+ +2 peaks in comparison
spectrum. It also showed a peak for carbonyl (C=O) at 1674cm−1. with M+ peaks were in the ratio 1:3. In mass spectra of
1
The H NMR spectrum of the compound 6 showed singlets at compounds I–X, the peak due to 1,2,4-triazolo [4,3-a]
d 3.79ppm, 4.95ppm and 8.56ppm due to OCH3, NH2 and NH, quinazoline cation appeared at m/z 168. In addition, a common
respectively, and a multiplet at d 6.82–8.06ppm was observed for peak at m/z 144, corresponding to the quinazolin-4-one moiety,
aromatic (8H) protons. Data from the elemental analyses were appeared in all mass spectra. Elemental (C, H, N) analysis
found to be in accord with the assigned structure. Further, the satisfactorily confirmed the elemental composition and purity
molecular ion recorded in the mass spectrum was also in agree- of the synthesized compounds. The physical data of the title
ment with the molecular weight of the compound.
compounds is presented in Table 1.
The title compounds I–X were obtained in fair to good
Ten compounds containing the 1,4-disubstituted [1,2,4]
yields through the cyclization of 6 with a variety of one-carbon triazolo quinazoline ring system were evaluated for their in-vivo
donors such as formic acid, acetic acid, propionic acid, butyric antihistamine activity. Histamine causes bronchospasm and
acid and chloroacetyl chloride at reflux. The formation of a guinea-pigs are the most susceptible animals to histamine. The
cyclic product was indicated by the disappearance of peaks due effect of the test compounds against histamine-induced bron-
to NH and NH2 of the starting material at 3350–3320 cm−1 in chospasm in conscious guinea-pigs was therefore determined.
Table 1 Characterization data of 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-ones
Compound
R
R¢
% Yield
Mp (°C)
Elemental analysis calculated/found
%C
%H
%N
I
-H
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-Cl
72
72
76
72
80
90
89
77
82
80
248–250
245–248
220–224
210–214
254–255
228–231
316–319
267–270
233–234
244–247
65.75
65.31
66.66
66.23
67.49
67.41
68.25
68.33
59.92
60.66
60.72
60.97
61.84
61.89
62.87
62.94
63.81
63.86
55.67
55.63
04.14
04.42
04.61
04.62
05.03
05.06
05.43
05.39
03.84
04.61
03.06
03.09
03.57
03.48
04.03
04.07
04.46
04.51
02.92
02.96
19.17
19.46
18.29
18.10
17.49
17.51
16.76
16.71
16.44
16.84
18.88
18.19
18.03
18.11
17.25
17.33
16.64
16.57
16.23
16.32
II
-CH3
III
IV
V
-CH2CH3
-(CH2)2CH3
-CH2Cl
-H
VI
VII
VIII
IX
X
-CH3
-Cl
-CH2CH3
-(CH2)2CH3
-CH2Cl
-Cl
-Cl
-Cl

Novel H1-antihistamine agents
1255
Table 2 Antihistamine and sedative/hypnotic activity of compounds I–X
Compound
Time of onset
Protection (%)
CNS depression (%)
of convulsion (s)
30 min
1 h
2 h
3 h
I
II
III
IV
V
VI
VII
VIII
382 4.23a
388 5.16a
387 7.25a
371 5.08a
369 4.24a
394 6.20a
423 12.25a
392 6.79a
387 8.20a
380 8.46a
398 29.50a
69.00 1.48a
71.00 1.25a
70.00 1.69a
68.00 1.45a
68.00 1.49a
70.00 1.19a
72.00 1.29a
70.00 1.54a
70.00 1.38a
69.00 1.60a
71.00 1.36a
2
3
3
3
3
3
4
5
6
4
1.47a
1.44a
1.54c
1.90a
1.90a
1.61a
1.83a
1.90a
2.25a
1.21b
3
5
6
6
4
9
9
1.37a
1.39b
1.70c
1.57a
1.85a
1.71a
1.83a
6
7
7
7
5
1.55a
1.37c
1.80c
1.39b
1.58a
4
5
4
6
4
7
8
1.41b
1.61b
1.74c
1.22b
1.57b
1.61b
2.54b
10 1.92a
12 2.06a
13 1.48c
10 1.72b
13 1.30c
32 1.71d
11 1.85b
10 1.88c
IX
X
9
8
1.87b
1.19c
8
6
1.89b
1.26c
Chlorpheniramine
11 1.93a
37 1.80d
22 1.97d
Data are expressed as mean s.d. from six different experiments done in duplicate. aP < 0.5, bP < 0.1, cP < 0.05 and dP < 0.001. In all cases, a signifi-
cance level of P < 0.05 was observed.
The advantage of this method is that it is non-invasive and the maleate. Interestingly, compounds II and VII also showed
animals are recovered after the experiment.
negligible sedation (5% and 8%, respectively) compared with
All the test compounds were found to exhibit good antihis- chlorpheniramine maleate (25%) and could therefore serve as
tamine activity (Table 2). Percentage protection data showed lead molecules for further modification to obtain a clinically
that all compounds offered significant protection, over the useful novel class of non-sedative antihistamines.
range of 68–72%. Structure–activity relationship studies indi-
cated that different substituents on the N-4 aromatic ring
exerted varied biological activity. The electronic nature of the
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